The integrin alphaEbeta7 is expressed on T cells, mast cells and dendritic cells (DCs) and binds to the E-cadherin to mediate T cell/epithelial cell specific adhesion. Furthermore, alphaE-/- mice have reduced numbers of intestinal intraepithelial T cells versus alphaE+/+ mice, indicating the importance of this interaction in vivo. In addition, there is another alphaEbeta7 ligand on intestine derived endothelial cells, whose distribution is not known. To evaluate the role of alphaEbeta7 in vivo, CD4+CD45RBhi T cells were transferred into scid/scid mice to generate Th1 biased intestinal inflammation. This syndrome was abrogated by administration of an anti-alphaEbeta7 monoclonal antibody. In contrast, when the alphaE+/+ recipient mice were reconstituted with alphaE-/- versus alphaE+/+ donor T cells, limiting the impact of alphaE deficiency to the T cell, disease severity was only modestly ameliorated. Finally, in the Th1 biased intestinal inflammation that develops in IL-10-/- mice, clinical signs of intestinal inflammation were accelerated in alphaE-/- versus alphaE-/- mice, a condition in which all cells are alphaE deficient. Overall, these studies suggest that there is another cell type, in addition to T cells, that modulates intestinal inflammation, and that when these non-T cells are alphaEbeta7 deficient, Th1 cytokine based intestinal inflammation is worsened. Importantly, in in vitro studies, naive CD4+ T cells produced more Th1 and less Th2 cytokines when stimulated in the presence of DCs derived from alphaE-/- versus alphaE+/+ mice. This finding suggests that when DCs are alphaE deficient, Th1 biased intestinal inflammation is worse, possibly through altered DC localization, function or interactions with T cells. In AIM 1, the phenotype, cytokine expression and distribution of alphaEbeta7+ DCs will be determined by flow cytometry, ELISA and immunohistochemistry. In AIM 2, the impact of alphaEbeta7 deficiency upon the course of the CD4+CD45RBhi T cell transfer model of intestinal inflammation will be determined when alphaEbeta7 deficiency is restricted to non-T cells in recipient mice, by clinical and microscopic evaluation. In AIM 3, the role of alphaEbeta7 in regulating DC cytokine expression or surface phenotype will be evaluated following direct stimulation, with or without alphaEbeta7 crosslinking, or after stimulation in T cell/DC co-cultures, using ELISA and flow cytometry. In AIM 4, the possible expression of E-cadherin or of other alphaEbeta7 ligands on naive or recently activated T cells will be assessed, by FACS or Northern blot. In addition, the roll of alphaEbeta7 in DC/T cell interactions will be determined using adhesion and co-stimulation assays. These experiments will provide insight into the impact of integrin alphaEbeta7 in DC localization and function relevant to Th lymphocyte differentiation, which have particular relevance to the intestine where cytokine dysregulation leads to inflammation.